Ke-Da Yu

Glutathione S-transferase M1 polymorphism and breast cancer susceptibility: a meta-analysis involving 46,281 subjects

Published data on the association between present/null polymorphism of glutathione S-transferase M1 (GSTM1) and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the GSTM1 present/null polymorphism and breast cancer risk. The pooled ORs were performed for null versus present genotype. A total of 59 studies including 20,993 cases and 25,288 controls were involved in this meta-analysis. Overall, significantly elevated breast cancer risk was associated with null genotype when all studies were pooled into the meta-analysis (ORxa0=xa01.10, 95% CIxa0=xa01.04–1.16). In the subgroup analysis by ethnicity, significantly increased risks were found for Caucasians (ORxa0=xa01.05, 95% CIxa0=xa01.00–1.10) and Asians (ORxa0=xa01.21, 95% CIxa0=xa01.08–1.35). When stratified by population-based studies or hospital-based studies, statistically significantly elevated risks were found among population-based studies (ORxa0=xa01.11, 95% CIxa0=xa01.03–1.20). In the subgroup analysis by menopausal status, statistically significantly increased risks were found among postmenopausal women (ORxa0=xa01.15, 95% CIxa0=xa01.04–1.28). In conclusion, this meta-analysis suggests that the GSTM1 null genotype is a low-penetrant risk factor for developing breast cancer.

Lack of association of CYP1A2-164 A/C polymorphism with breast cancer susceptibility: a meta-analysis involving 17,600 subjects

Published data on the association between cytochrome P-450 1A2 (CYP1A2)-164 A/C polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between CYP1A2-164 A/C polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (AC versus AA, CC versus AA), dominant model (CCxa0+xa0AC versus AA), and recessive model (CC versus AAxa0+xa0AC), respectively. A total of 9 studies including 7,580 cases and 10,020 controls were involved in this meta-analysis. Overall, no significantly elevated breast cancer risk was found in all genetic models when all studies were pooled into the meta-analysis (AC versus AA: ORxa0=xa01.02, 95% CIxa0=xa00.92–1.13; CC versus AA: ORxa0=xa01.17, 95% CIxa0=xa00.83–1.64; dominant model: ORxa0=xa01.07, 95% CIxa0=xa00.93–1.23; and recessive model: ORxa0=xa01.13, 95% CIxa0=xa00.82–1.55). In the subgroup analysis by ethnicity or source of controls, there was still no significant association detected in all genetic models. In conclusion, upto date, there is still no enough evidence to indicate the association of CYP1A2-164 A/C polymorphism and breast cancer development.

XRCC3 5′-UTR and IVS5-14 polymorphisms and breast cancer susceptibility: a meta-analysis.

Published data on the association between XRCC3 5′-UTR and IVS5-14 polymorphisms and breast cancer risk are inconclusive. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. Crude ORs with 95% CIs were used to assess the strength of association between these polymorphisms and breast cancer risk. The pooled ORs were performed for codominant model, dominant model, and recessive model, respectively. A total of four studies were involved in the meta-analysis with 6,303 cases and 6,563 controls for XRCC3 5′-UTR polymorphism and with 6,270 cases and 6,682 controls for XRCC3 IVS5-14 polymorphism. For XRCC3 5′-UTR A/G polymorphism, significantly elevated breast cancer risk was associated with variant genotype when all studies were pooled into the meta-analysis (AG vs. AA: ORxa0=xa01.11, 95% CIxa0=xa01.03–1.19; dominant model: ORxa0=xa01.09, 95% CIxa0=xa01.01–1.17). For XRCC3 IVS5-14 A/G polymorphism, significantly decreased breast cancer risk was associated with variant genotype (GG vs. AA: ORxa0=xa00.86, 95% CIxa0=xa00.77–0.96). In conclusion, this meta-analysis suggests that the variant G allele of XRCC3 5′-UTR polymorphism is a low-penetrant risk factor for developing breast cancer, while the variant G allele of XRCC3 IVS5-14 polymorphism has a protective effect on breast cancer development.

The associations between two polymorphisms in the interleukin-10 gene promoter and breast cancer risk

The association between single-nucleotide polymorphisms (SNPs) in the interleukin-10 (IL-10) gene promoter and breast cancer risk is still ambiguous. We here performed a meta-analysis based on the evidence currently available from the literature to make a more precise estimation of the relationship between two genetic variants in the IL-10 gene promoter, −1082Axa0>xa0G (rs1800896) and −592Cxa0>xa0A (rs1800872), and breast cancer. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the corresponding strengths of association under the codominant, dominant, and recessive models. A total of ten studies (4,181 cases and 4,384 controls) were eligible for meta-analysis. There were six studies with 3,032 cases and 3,190 controls for rs1800872, and eight studies with 1,636 cases and 1,670 controls for rs1800896. Meta-analysis showed that neither of the two polymorphisms had any association with increased breast cancer risk (for rs1800896: ORxa0=xa01.060, 95% CIxa0=xa00.785–1.432 in the dominant model, and ORxa0=xa01.152, 95% CIxa0=xa00.958–1.386 in the recessive model; and for rs1800872: ORxa0=xa00.952, 95% CIxa0=xa00.859–1.056 in the dominant model, and ORxa0=xa00.892, 95% CIxa0=xa00.741–1.072 in the recessive model). The results did not change when the analyses were restricted in Caucasians, or in the studies fulfilling Hardy–Weinberg equilibrium, or according to source of controls. In outlier analysis, no individual study affected the overall OR dominantly, since omission of any single study made no material huge difference. In conclusion, the present meta-analysis suggests a lack of association between the two SNPs (rs1800896 and rs1800872) in the IL-10 gene promoter and breast cancer risk. Further studies, either with larger sample size or regarding other SNPs/haplotypes within the IL-10 gene, are needed to clarify the role of IL-10 in breast carcinogenesis.

The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next-generation sequencing

To characterize the prevalence of BRCA mutations and characteristics of BRCA carriers in China and to update the clinical recommendations for BRCA testing, we conducted a wide screen for BRCA mutations using next‐generation sequencing (NGS). A total of 4,034 Chinese subjects were screened for germline BRCA1/2 mutations, including 2,991 breast cancer patients and 1,043 healthy individuals from the community enrolled as controls. We developed an NGS‐based approach to perform BRCA1/2 screening. BRCA mutations were identified in 9.1% (232/2,560) of cases with at least one risk factor, in 3.5% (15/431) of sporadic patients and in 0.38% (4/1,043) of healthy controls. The mutation frequency ranged from 8.9 to 15.2% in cohorts with a single risk factor to 16.6–100% in groups with multiple risk factors. We identified 70 novel BRCA mutations. A high frequency of BRCA1 c.5470_5477del was detected, accounting for 13.9% (16/115) of the BRCA1 mutations detected in our study. Clinical characteristics such as family history, invasive carcinoma, negative human epidermal growth factor receptor 2 (HER2), high Ki67 index, lymph node status, and high tumour grade were closely related to BRCA mutations. BRCA2 carriers had poorer disease‐free survival among HER2‐ or hormone receptor‐positive patients (hazard ratio = 1.892; 95% confidence interval: 1.132–3.161; p = 0.013). This study shows that BRCA mutation carriers could be frequently identified among breast cancer patients with multiple risk factors. Importantly, we established an NGS‐based pipeline for BRCA1/2 testing in clinical practice and strongly suggest that breast cancer patients of premier‐ and moderate‐grade risks receive BRCA1/2 mutations testing in China.

Five common single nucleotide polymorphisms in the PALB2 gene and susceptibility to breast cancer in eastern Chinese population.

Certain rare germline mutations in the PALB2 gene have been confirmed to increase susceptibility to breast cancer in diverse populations, but it has not been very clear that whether some common polymorphic variants in PALB2 also increase breast cancer risk. We conducted a case–control study to validate the association of common variations in the PALB2 gene and breast cancer in eastern Chinese population. A total of six common single nucleotide polymorphisms (rs8053188, rs16940342, rs249954, rs447529, rs249935, and rs3096145), which tagged the known common variants (minor allele frequency >0.1) of PALB2, were genotyped among 660 cases and 756 cancer-free controls by SNPstream assay. Except rs3096145, other five SNPs passed the quality assessment criteria with genotyping call rate >95%. Genotype and allele frequencies were statistically different between cases and controls for PALB2 rs447529 and rs249935. PALB2 rs249935 G allele was related to a 1.21-fold (95% confidence intervalxa0=xa01.02–1.43) increase in risk for each ‘A’ allele carried (Pxa0=xa00.029). Based on the dominant inheritance model tests, we found that compared with rs447529 CC homozygotes, the variant homozygote GG and heterozygote GC carriers had a 0.43-fold decreased risk of breast cancer (95% confidence intervalxa0=xa00.24–0.78, Pxa0=xa00.005). Combined with the results of the former study, our findings further verified that some common PALB2 polymorphisms may contribute to the etiology of breast cancer in Chinese women, so other large studies are warranted to confirm these observations in different ethnic populations.

Abstract P1-12-02: Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial

Background: Whether administration of LHRH analog during CT in premenopausal patients with early-stage, hormone receptor-positive disease would reduce CT-induced premature ovarian failure (POF) is still controversial. Moreover, whether LHRH analog would influence the prognosis of patients is unknown yet. This randomized study is to evaluate whether administration of LHRH analog during CT would reduce POF and effect the prognosis of breast cancer. Methods: This is arandomized, controlled phase III clinical trial. Premenopausal patients age Results: Between 2/09 and 5/13, the trial has finished enrollment, 216 patients were enrolled. The median age were 37.5 in combined arm (n=108) and 39 in sequential arm (n=108), respectively. The median follow-up time was 27.4 months and 25.7 months, respectively. 15 patients and 21 patients received neoadjuvant CT, respectively. There were no significant difference in age, tumor stage and CT regimens (p>.05). The median cycles of GN were 25, respectively. 47% had complete primary endpoint data. POF rate were 5/42 (11.9%) in the combined arm and 16/60 (26.7%) in the sequential arm. POF rate (and post-menopausal FSH) rate were 1/42 (2.4%) in the combined arm and 8/60 (13.3%) in the sequential arm. In neoadjuvant CT subgroup, each has 1 patient achieved pathological complete remission, and there was no significant difference in objective clinical response. There were 9 patients in the combined arm and 3 patients in the sequential arm had occured RFS events (including 2 and 0 deaths, respectively, OR=3.18, 95%CI:0.84-12.09, P=.075). Conclusions:LHRH analog administration with CT might be associated with less POF and did not affect the efficacy of neoadjuvant CT, however, had no RFS benefit, it may need longer follow-up. We will conduct an interim analysis in November 2014. Clinicaltrials.gov Registry Number: NCT01712893. Citation Format: Jian-Wei Li, Guang-yu Liu, Ke-Da Yu, Ya-jie Ji, Miao Mo, Li Lei, Jiong Wu, Gen-hong Di, Yi-feng Hou, Zhen Hu, Can-ming Chen, Zhen-Zhou Shen, Zhi-Ming Shao. Effect of using LHRH analog during chemotherapy (CT) on premature ovarian failure and prognosis in premenopausal patients with early-stage, hormone receptor-positive breast cancer: The primary analysis of a randomized controlled phase III trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-12-02.

Influence of delayed initiation of adjuvant chemotherapy on breast cancer survival is subtype-dependent.

Purpose The optimal time from surgery to initiation of adjuvant chemotherapy of breast cancer is still controversial. We investigated the influence of time to adjuvant chemotherapy on survival outcomes according to breast cancer subtype. Results Longer delay of initiation of adjuvant chemotherapy (≤4 weeks versus >8 weeks)) significantly decreased the DFS (adjusted hazard ratio [HR] of 1.86; 95% confidence interval [CI], 1.19-2.90) and OS (adjusted HR of 2.02; 95% CI, 1.10-3.71). However, a moderate delay (≤4 weeks versus 4-8 weeks) did not significantly influence the survival. We further investigated the effect of time to adjuvant chemotherapy (≤8 versus >8 weeks) on survival according to subtypes. Patients with luminal-A tumors who received delayed chemotherapy had no increased risk of recurrence (HR of 1.15; 95% CI, 0.54-2.43). In contrast, patients with luminal-B, triple-negative, or trastuzumab-untreated HER2-positive tumors would have decreased DFS because of delayed chemotherapy, with HR of 1.93 (95% CI, 1.10-3.34), 2.55 (95% CI, 1.25-5.18), and 2.41 (95% CI, 1.36-4.26), respectively. Methods Operable women with stage I-IIIa breast cancer between 2003 and 2006 in our institution were included. 1,408 patients were divided into 3 groups according to the time to adjuvant chemotherapy: ≤4 weeks, 4-8 weeks, and >8 weeks. Disease-free survival (DFS) and overall survival (OS) were calculated. Conclusion Longer delay of adjuvant chemotherapy was associated with worse survival and early initiation of adjuvant chemotherapy should be performed for patients with aggressive tumor subtypes.

Abstract P1-04-04: Activating HER2 mutations promote oncogenesis and resistance to HER2-targeted therapies in breast cancer

Purpose: Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor2 ( HER2 ) have been reported to lead to resistance to HER2-targeted therapies in HER2-positive breast cancer, while activating mutations of HER2 have been described in HER2-negative breast cancer. The prevalence, clinicopathological characteristics, and phenotypes of HER2 mutations are not well established, thus we sought to describe the HER2 mutation profile of Chinese breast cancer patients. Methods: DNA samples were gathered from breast cancer patients undergoing neoadjuvant (N=102) or adjuvant therapy (N=498) at Fudan University Shanghai Cancer Center between January 1, 2006 and December 31, 2012. Sanger sequencing was performed to analyze all exons of HER2 to identify somatic mutations. To determine the phenotypes of novel HER2 mutations, in vitro kinase assays, protein structure analysis, cell culture, and xenograft experiments were conducted. Results: 10 HER2 somatic mutations were observed in 17 patients (17/600, 2.83%). 7 novel HER2 mutations were uncovered, 4 in the transmembrane domain and 3 in the kinase domain. Kinase domain mutations L768S and V773L were detected in HER2-negative tumors, while K753E was found in HER2-positive disease. In vitro kinase assays found that L768S and V773L exhibited a significant increase of tyrosine kinase-specific activity, while Western blots showed that L768S and V773L strongly increased phosphorylation of all signaling proteins in both MCF10A and MCF7cell lines, indicating that they were activating mutations. In Matrigel cultures, L768S and V773L formed acini when seeded in vehicle, but maintained spherical morphology when seeded in culture containing trastuzumab. The addition of lapatinib in Matrigel culture inhibited the growth of all except K753E, which was successfully inhibited by neratinib. Similarly, L768S, V773L and K753E increased the number of cell colonies formed in soft agar, trastuzumab and lapatinib treatment decreased the number of colonies formed by L768S and V773L, but only neratinib could inhibit the colony growth of K753E. Xenograft showed L768S and V773L displayed a more rapid growth, while K753E showed resistance to lapatinib in vivo. MCF10A cells bearing K753E mutation were found to be resistant to lapatinib (IC50>10,000 nmol/L), but could be inhibited by neratinib, though requiring a relatively higher dosage (IC50 of 32 nmol/L) than HER2 WT (IC50 of 480 nmol/L for lapatinib, HER2 mutations. Meanwhile, clinical follow-up showed that the 2 patients with K753E mutation who received adjuvant trastuzumab treatment presented with either brain or bone metastasis, in their 3rd and 5th year after initial cancer diagnosis, suggesting K753E mutation may have a role in trastuzumab resistance as well. Conclusions: HER2 somatic mutations were found in 2.83% of patients in this study. HER2-positive tumors harboring certain HER2 kinase domain resistance mutations may not benefit from trastuzumab or lapatinib treatment, and neratinib may offer an alternative treatment option for these patients. HER2-negative disease with activating mutations may benefit from HER2-targeted therapies, and may be of interest in prospective clinical trials. Citation Format: Wen-Jia Zuo, Yi-Zhou Jiang, Ke-Da Yu, Zhi-Ming Shao. Activating HER2 mutations promote oncogenesis and resistance to HER2-targeted therapies in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-04-04.

The effect of delayed adjuvant chemotherapy on relapse of triplenegative breast cancer

BackgroundnFor triple negative breast cancer (TNBC), the optimal time from surgery to initiation of adjuvant chemotherapy is controversial. We investigated the influence of time to adjuvant chemotherapy on outcome in TNBC patients.nnnMethodsnFemale patients with stage I-IIIa operable TNBC between 2006 and 2008 in our institutions were included. A total of 331 patients were divided into 3 groups according to the time to adjuvant chemotherapy: ≤30, 31-60, and >60 days. Relapse free survival (RFS) were calculated and compared.nnnResultsnProlonged delay of initiation of adjuvant chemotherapy (≤30 versus >60 days) significantly decreased the RFS in our TNBC cohort [adjusted hazard ratio (HR) of 2.39; 95% confidence interval (CI), 1.13-5.07, P=0.02]. While a moderate delay (≤30 versus 31-60 days) did not significantly influence RFS in all TNBC patients, it did compromise survival in lymph node positive patients (P=0.04).nnnConclusionsnLonger delay of adjuvant chemotherapy was associated with worse survival in TNBC patients. Early initiation of adjuvant chemotherapy should be considered, especially for relatively high risk node positive TNBCs.